Cardiovascular effects of cocaine are being extensively studied using various species of animals as model systems. For all the conscious species studied, cocaine (0.03-3.0 mg/kg, i.v.) produces a dose-dependent and prolonged increase in mean arterial blood pressure and heart rate. Studies in rats have shown that inhibition of peripheral sympathetic neuronal amine uptake mechanism by cocaine is not critical for initiating cocaine's pressor, tachycardiac and plasma catecholamine increasing effects and that central stimulation of the sympathoadrenal neural axis activity plays an important role in these effects. The peak pressor effect of cocaine is mediated by norepinephrine of sympathetic neural origin and the peak tachycardiac effect of cocaine is mediated by epinephrine of adrenal medullary origin. To investigate the role of the cocaine metabolites in cocaine toxicity, we have also investigated the hemodynamic and cardiac-electrophysiological effects of cocaine and its metabolites in anesthetized, artificially-ventilated rats during continuous i.v. infusions. At the highest dose (1.5 mg/kg/min), cocaine decreased blood pressure and heart rate, while QRS duration, an index of cocaine's local anesthetic effect, was increased. Cocaethylene, a metabolite produced following co-administration of cocaine and ethanol, had effects comparable to those of cocaine. The cocaine metabolite norcocaine produced a decrease in blood pressure at lower doses, which reversed to a small increase at the higher dose. The higher dose of norcocaine clearly decreased heart rate and increased QRS duration. The cocaine metabolites benzoylecgonine and ecgonine methyl ester increased blood pressure at the higher dose without affecting either heart rate or QRS duration. These results suggest that the accumulation of the persistent, active metabolites benzoylecgonine and ecgonine methyl ester may contribute to delayed-onset, cocaine-related toxicity.